Cleviprex is indicated for the rapid reduction of blood pressure in the perioperative setting.

4.2 Posology and method of administration

Adults/Elderly

Clevidipine is intended for intravenous use. Titrate drug to achieve the desired blood pressure reduction. Individualise dosage depending on the blood pressure to be obtained and the response of the patient. Blood pressure and heart rate must be monitored continually during the infusion, and then until vital signs are stable. Patients who receive prolonged clevidipine infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after infusion is stopped.

Initial dose: Initiate the intravenous infusion of clevidipine at 4 ml/h (2 mg/h); the dose may be doubled every 90 seconds. Continue titration until desired target range is achieved.

Maximum dose: Most patients in clinical studies were treated with doses of 32 ml/h (16 mg/h) or less. The maximum recommended dose is 64 ml/h (32 mg/h). There is limited clinical experience in doses over 64 ml/h (32 mg/h). No more than 1000 ml of clevidipine infusion is recommended per 24-hour period due to the associated lipid load. There is limited experience with clevidipine infusion durations beyond 72 hours at any dose.

Transition to an oral antihypertensive agent: Discontinue clevidipine or titrate downward while appropriate oral therapy is established. When an oral antihypertensive agent is being instituted, consider the lag time of onset of the oral agent's effect. Continue blood pressure monitoring until desired effect is achieved. Discontinuation of Cleviprex leads to a reduction in antihypertensive effects within 5 to 15 minutes.

Instructions for use

Strict aseptic technique must be maintained while handling Cleviprex. Cleviprex is a single-use parenteral product that contains phospholipids and can support the growth of microorganisms. Do not use if contamination is suspected. Once the stopper is punctured, use within 12 hours and discard any unused portion.

Cleviprex is a sterile, white opaque emulsion. Visually inspect for particulate matter and discolouration prior to use. Solutions that are discoloured or contain particulate matter should not be used.

Gently invert vial before use to ensure uniformity of the emulsion prior to administration.

Clevidipine should be administered via a vented spike and infusion device.

Clevidipine may be administered using a syringe or volumetric pump. Commercially available standard plastic cannulae may be used to administer the infusion. Clevidipine can be administered via a central line or a peripheral line.

Clevidipine should not be administered in the same intravenous line as other medications.

Hepatic Impairment

Data regarding the dosage regimen in patients with hepatic impairment are limited and have not been specifically studied. In clinical trials, 78 (6.0%) patients with abnormal hepatic function (defined as total bilirubin > 1.5 ULN, AST/SGOT, and/or ALT/SGPT > 2ULN for non surgical patients and > 3 ULN for surgical patients) were treated with clevidipine. No dose adjustment is required in patients with hepatic impairment.

Renal Impairment

Data regarding the dosage regimen in patients with renal impairment are limited and have not been specifically studied. In clinical trials 121 (9.2%) patients with moderate to severe renal impairment were treated with clevidipine. No dose adjustment is required in patients with renal impairment.

Paediatric population

The safety and efficacy of clevidipine in children aged 0 to 18 years old has not yet been established. No data are available.

Patients on other lipid-based therapies

Cleviprex contains approximately 0.2 g of lipid per ml (8.4 kJ/2.0 kcal). In patients with lipid load restrictions the quantity of concurrently administered lipids may need to be adjusted to compensate for the amount of lipid infused as part of the clevidipine formulation.

4.3 Contraindications

Hypersensitivity to the active substance, soybeans, soya-bean oil refined, soy products, peanut, eggs or egg products or to any of the other excipients listed in section 6.1.

Clevidipine must not be used in patients with defective lipid metabolism such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia.

4.4 Special warnings and precautions for use

Use strict aseptic technique and discard any unused product within 12 hours of stopper puncture. Failure to practice appropriate aseptic technique may lead to contamination of infused product and the potential for systemic infection.

Hypotension and reflex tachycardia

Rapid pharmacologic reductions in blood pressure may produce systemic hypotension and reflex tachycardia. If either occurs with clevidipine, consider decreasing the dose by half or stopping the infusion.

Patients with aortic stenosis, hypertrophic obstructive cardiomyopathy, mitral stenosis, aortic dissection or pheochromocytoma have not been studied in clinical trials with clevidipine.

Clevidipine should not be used in patients with uncorrected critical aortic stenosis because excessive afterload reduction can reduce myocardial oxygen delivery. For patients undergoing surgery to relieve their stenosis with a replacement valve, clevidipine may be useful in the post-operative period if the ability to compensate for decreases in blood pressure has been restored.

Patients with hypertrophic obstructive cardiomyopathy and mitral stenosis may also be at risk of reduced oxygen delivery.

Clevidipine should be used with caution in patients who cannot increase their heart rate adequately to compensate for reduced blood pressure such as those with left bundle-branch block or primary ventricular pacing.

There are limited data for use of clevidipine in acute myocardial infarction or acute coronary syndrome.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed as pharmacokinetic drug interactions are unlikely given clevidipine is metabolised by hydrolysis in vivo.

Inhibition of CYP isoforms was detected in in vitro studies at concentrations equivalent to at least 10 times the highest concentration typically seen in the clinic. At the doses recommended, clevidipine and its major dihydropyridine metabolite do not have the potential for inhibiting or inducing any CYP enzyme.

Patients receiving oral or IV anti-hypertensive agents, including betablockers, while on clevidipine should be observed closely for increased anti-hypertensive effects.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of clevidipine in pregnant women.

Studies in animals have shown effects on embryo-/fetal development and parturition (see section 5.3)

Clevidipine should not be used during pregnancy unless clearly necessary.

Lactation

It is unknown whether clevidipine is excreted in human breast milk. The excretion of clevidipine in milk has not been studied in animals. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with clevidipine should be made taking into account the benefit of breastfeeding to the child and the benefit of clevidipine therapy to the woman.

Fertility

Clevidipine had no adverse effects on fertility or mating behaviour of male rats. Pseudopregnancy and changes in oestrus cycle were observed in female rats.

4.7 Effects on ability to drive and use machines

Cleviprex has moderate influence on the ability to drive and use machines.

Clevidipine may cause dizziness which could interfere with the ability to drive or operate machinery; however, patients receiving Cleviprex will be confined to hospital for the duration of treatment.

4.8 Undesirable effects

Clevidipine has been evaluated for safety in 1,423 hypertensive patients. Infusion rate was evaluated for 1,326 patients among whom 6% were treated with the mean dose of >32 ml/h (16 mg/h) and up to the maximum recommended therapeutic dose of 64 ml/h (32 mg/h). Continuous infusion duration was evaluated for 1,380 patients 20% of whom were continuously infused for more than 15 hours and up to 72 hours. The incidence of adverse reactions showed no association with gender, age, race or ethnicity.

Atrial fibrillation, sinus tachycardia and hypotension were all frequently observed adverse events in the perioperative population. These events may also be related to the surgical procedures being undertaken rather than the drug treatment.

In clinical studies, a total of 2.5% of patients receiving clevidipine experienced oxygen saturation decrease (reported as hypoxia) compared to rates of 1.5% for nitroglycerine (NTG) and, 5.1% for sodium nitroprusside (SNP) and 5.7% for nicardipine (NIC).

In all Phase III clinical trials on cardiac surgical patients, the incidence of atrial fibrillation in patients treated with Cleviprex as compared to active comparators and placebo was 32.8%, 32.9%, and 12.0%, respectively, among which 3.9%, 2.5%, and 0.0% were considered treatment related. The incidence of sinus tachycardia in perioperative patients treated with Cleviprex as compared to active comparators and placebo was 25.5%, 30.5%, and 0.0%, respectively, among which 1.3%, 1.2%, and 0.0% were considered treatment related. The incidence of hypotension in perioperative patients treated with Cleviprex as compared to active comparators and placebo was 15.1%, 14.9%, and 1.0%, respectively, among which 2.5%, 2.5%, and 0.0% were considered treatment related.

The adverse reactions (Table 1: Perioperative hypertension) reported in excess (>0.5%) in patients receiving placebo and as more than an isolated case in patients receiving clevidipine in controlled clinical trials are listed below as MedDRA preferred term by system organ class and absolute frequency.

Frequencies are defined as: very common ≥1/10; common ≥1/100, <1/10; uncommon ≥1/1000, <1/100; rare ≥1/10000, <1/1000; very rare <1/10000; not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In clinical studies in patients in non-perioperative settings (n=294) the following additional adverse reactions were seen in patients treated with clevidipine: hypersensitivity (uncommon), flushing (common), feeling hot (common) and polyuria (common).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

The maximum recommended dose is 64 ml/h (32 mg/h). In clinical trials, 1 healthy subject received a dose of clevidipine up to 212 ml/h (106 mg/h) and experienced mild flushing and a slight transient increase in serum creatinine.

As a result of a weight-based regimen, 49 patients received a maximum rate above 64 ml/h (32 mg/h) without any clinical difference in the incidences of adverse events compared to those who received 64 ml/h (32 mg/h) or below. The average dose in these patients was 82 ml/h (41 mg/h) with a maximum dose of 120 ml/h (60 mg/h).

One cardiac surgical patient received a bolus dose of clevidipine prior to aortic cannulation and experienced hypotension.

An overdose of clevidipine may result in tachycardia or excessive reduction in blood pressure. If either occurs with clevidipine, consider decreasing the dose by half or stopping the infusion. Discontinuation of clevidipine leads to a reduction in antihypertensive effects within 5 to 15 minutes.

Pharmacodynamic effects: Clevidipine is titrated to the desired reduction in blood pressure.

In the perioperative patient population, clevidipine produces a 4-5% reduction in systolic blood pressure (SBP) within 2-4 minutes after starting a 0.4 mcg/kg/min infusion (approximately 2-4 ml/h [1-2 mg/h]). In studies up to 72 hours there was no evidence of tolerance.

In most patients, full recovery of blood pressure is achieved in 5-15 minutes after the infusion is stopped. In studies of up to 72 hours of continuous infusion, in patients that were not transitioned to other antihypertensive therapies, there was some evidence of rebound hypertension following clevidipine discontinuation.

An increase in heart rate can be a normal response to rapid decreases in blood pressure; in some patients the heart rate response may be pronounced.

The effect of clevidipine in anaesthetised cardiac surgery patients on central haemodynamics, myocardial blood flow and metabolism have been studied. In these patients, cardiac output and stroke volume increased by 10%. As the dose of clevidipine was escalated, myocardial oxygen extraction decreased significantly, indicating preservation of myocardial perfusion and a direct coronary vasodilatory effect. No increase in net lactate production in coronary sinus blood was observed, confirming the absence of myocardial ischaemia due to coronary steal.

The adverse events observed during the treatment infusion period up to 1 hour after the end of the infusion were similar in patients who received clevidipine and in those who received comparator agents. The incidence of adverse events leading to study drug discontinuation in patients with perioperative hypertension receiving clevidipine was 5.9% versus 3.2% for all active comparators.

Other trials

Additional preliminary studies have been conducted in patients with essential hypertension, severe hypertension and in acutely hypertensive patients with acute intracerebral haemorrhage.

The pharmacodynamic relationship between clevidipine and blood pressure was measured in a randomised placebo-controlled, single-blind trial of 61 patients with mild to moderate essential hypertension (Mean Blood Pressure BP 151/86). The results showed clevidipine had a high clearance, induced dose-dependent reductions in systolic BP (SBP), Diastolic BP (DBP) and Mean Arterial Pressure (MAP), and had a linear relationship between concentration and BP response.

The effect of clevidipine on severe hypertension (BP >180/115) was studied in an open-label trial in 126 patients (VELOCITY). Mean infusion duration was 21 hours; A mean decrease in SBP of 21.1% was achieved in 89% of patients within first 30 minutes; median time to achieve target SBP was 10.9 minutes; median dose to achieve target BP was 8 mg/hr.

The use of clevidipine in 33 patients with intracerebral haemorrhage and acute elevated blood pressure was studied in an open-label clinical trial (ACCELERATE). Within 30 minutes of initiation of clevidipine infusion, systolic blood pressure was reduced to within the target range (≥140 mmHg to ≤160 mmHg) in a median time of 5.5 minutes. Systolic blood pressure was reduced to ≤160 mmHg within the first 30 minutes after initiation of clevidipine infusion in 97% (32/33) patients.

5.2 Pharmacokinetic properties

Clevidipine is rapidly distributed and metabolised. The arterial blood concentration of clevidipine declines in a multiphasic pattern following termination of the infusion. The initial phase half-life is approximately 1 minute, and accounts for 85-90% of clevidipine elimination. The terminal half-life is approximately 15 minutes.

Distribution: Clevidipine is >99.5% bound to proteins in plasma at 37°C. The steady state volume of distribution is 0.17 L/kg in arterial blood.

Metabolism and elimination: Clevidipine is rapidly metabolised by hydrolysis of the ester linkage, primarily by esterases in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction. The primary metabolites are the carboxylic acid metabolite and formaldehyde formed by hydrolysis of the ester group. The carboxylic acid metabolite is inactive as an antihypertensive. This metabolite is further metabolised by glucuronidation or oxidation to the corresponding pyridine derivative. The clearance of the primary dihydropyridine metabolite is 0.03 L/h/kg and the terminal half-life is approximately 9 hours.

In vitro studies show that clevidipine and its metabolite at the concentrations achieved in clinical practice do not inhibit or induce any CYP enzyme.

In a clinical study with radiolabelled clevidipine, 83% of the drug was excreted in urine and faeces. The major fraction, 63-74% is excreted in the urine, 7-22% in the faeces. More than 90% of the recovered radioactivity is excreted within the first 72 hours of collection.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Findings in the repeated-dose studies were generally related to the pharmacology of clevidipine and/or the administration of high quantities of lipid vehicle. These effects are considered of little relevance to the shorter term clinical use.

Clevidipine displayed positive genotoxic potential in in vitro assays (Ames test, mouse lymphoma thymidine kinase locus assay, chromosomal aberration assay) but not in vivo in the mouse micronucleus test. The positive in vitro results are consistent with the formation of formaldehyde, a minor metabolite of clevidipine, which is known to be a genotoxic in vitro and a probable human carcinogen. However, human in vivo exposure to formaldehyde at the maximum clinical doses of clevidipine (64 ml/h [32 mg/h]) is at least several hundred times less than normal daily endogenous formaldehyde generation, and is therefore not of clinical concern.

Development and reproductive toxicity studies showed no adverse effects on fertility or mating behaviour of male rats; pseudopregnancy and changes in oestrus cycle were observed in female rats.

Increased post-implantation losses and dose-related decreases in ossification were seen in both rats and rabbits. In rats, a reduction in ossification of paws was observed that included partially ossified metacarpals, metatarsals and phalanges suggesting developmental retardation. Renal pelvic cavitation was also observed. In addition, malrotations of a hind limb were observed that were not considered related to skeletal alterations.

Rabbits exhibited a reduction in ossification of supraoccipital bones and sternebrae and unossified heads of longlimb bones. In addition, an increase in fused and/or misaligned sternebrae were observed. These effects are similar to changes reported with other calcium channel antagonists.

Rats dosed with clevidipine during late gestation and lactation experienced dose-related increases in mortality, length of gestation and prolonged parturition.

6. Pharmaceutical particulars

6.1 List of excipients

Soya-bean oil refined

Glycerol

Egg phospholipids

Oleic acid

Disodium edetate

Water for injections

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.

6.3 Shelf life

30 months refrigerated (2-8°C).

From a microbiological perspective the stopper should be punctured immediately before use and any remaining product discarded after 12 hours.

6.4 Special precautions for storage

Store and transport refrigerated (2°C – 8°C). Do not freeze1.

Keep vial in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

Lipid filters with a 1.2 micron pore size may be used when administering Cleviprex.

Cleviprex should not be diluted.

Cleviprex should not be administered in the same line as other medications; however, Cleviprex can be administered with the following:

• Water for injections

• Sodium Chloride (0.9%) Injection

• Sodium Chloride (0.45%) Injection

• 5 % glucose solution

• 5% glucose solution in Sodium Chloride (0.9%) Injection

• 5% glucose solution in Ringers Lactate Injection

• Lactated Ringers Injection

• 40 meq Potassium Chloride in 0.9% Sodium Chloride

• 10% amino acid

Compatibility may vary between products from different sources and health care professionals are advised to carry out appropriate checks when mixing Cleviprex emulsion for injection with other parenteral solutions.

Any unused product or waste material should be disposed of in accordance with local requirements.